The present invention is directed to the field of delivery of drugs and cosmetics through administration with a lipid carrier. More particularly, the invention describes the use of lipids as surfactants and excipient delivery vehicles.
The topical (including ocular, nasal, aural, vaginal, dermal, and transdermal) delivery of biologically active agents such as drugs is typically achieved by the use of anionic, nonionic, amphoteric or cryptoanionic surfactants such as sodium deoxycholate or propylene glycol. This use of surfactants is due to the typically poor absorption of drugs or biological agents by this route; absorption being enhanced by use of these surfactants. Such surfactants, such as for example synthetic emulsifiers, form gels at certain concentrations, for example, at concentrations of about 14% to 75%, (Table 1) and are thereby used as carriers and excipients by the cosmetics industry. These concentrations of surfactants heretofore required are generally irritating to the nasal mucosa. In contrast, materials used to form liposomes are non-irritating, but have heretofore not been shown to enhance drug absorption across membranes. The present invention discloses the use of a lipid delivery system at a relatively low lipid concentration as a non-toxic, non-irritating carrier or excipient alone or in combination with other agents, for both drugs and cosmetics.
Previous work in the area of surfactants employed to enhance uptake of drugs involved the use of bile salts and other surfactants (Gordon et al., 1985, Proc. Natl. Acad. Sci. 82:7419-7423; Hirai et al., 1981, Int. J. Pharm., 9:165-172; Duchateau et al., 1987, Int. J. Pharm., 39:87-92; and Hanson et al., 1986 IN:Delivery Systems for Peptid Drug, Davis, ed., Plenum Press, N.Y., pp, 233-242). As stated hereinabove, these salts and surfactants have been found to be toxic to nasal mucosa (Hirai et al., 1981, Int. J. Pharm., 9:173-184).
The present invention discloses a new non-irritating lipid excipient system that can be used in liquid sprayable or droppable form, or alternatively in a viscous liquid or gel form. The physical state of the excipient (e.g., liquid, viscous liquid, or gel) depends on the lipid and concentration thereof used, the pH of the system, and the concentration of salts in the system. The lipid excipient in sprayable or droppable form has special utility in the non-irritating delivery of peptides (e.g., calcitonin and insulin) and hormones (e.g. growth hormone) to the nasal mucosa, due to the ability of the excipient to enhance peptide absorption across nasal membranes. This enhancement of absorption across membranes can also be characterized as an enhancement of the cell penetrating properties of the excipient, as compared to standard, more toxic excipients (e.g. deoxycholate), (see FIG. 3). In addition to the delivery of peptides, the excipient can also be used to deliver hormones, antihistimines and nasal moisturizers, among other biologically active agents. The dissolution or suspension of biologically active agents in the gel excipient of the invention can also provide a sustained release of the agent at the site of application.
With regard to topical delivery of pharmaceuticals or cosmetics, the same excipient, in viscous liquid or gel form, when applied to the skin surface exhibits the desirable "slip", "playtime", and "resonance" characteristics of a cosmetic preparation. As such, the preparations made with the lipid excipient of the invention can include the application of cosmetic preparations such as sunscreens e.g., para-amino benzoic acid (PABA), and moisturizers. As gel excipients for biologically active agents such as pharmaceuticals, the suspension or dissolution of the agent in the gel can serve as a sustained release medium for delivery of the agent across membranes. These gels can be applied intra-nasally, intra-ocularly, intra-aurally, buccally, dermally, transdermally, rectally, or vaginally.
The lipids employed in the present invention are preferably phospholipids, more preferably lysophospholipids. Lysophospholipids have heretofore been improbable candidates for pharmaceutical and cosmetic surfactants or excipients due to their lytic effects on cells. The present invention is directed to non-toxic, non-irritating compositions of pharmaceutical and cosmetic excipients comprising lysophosphatide, specifically lysophosphatidylethanolamine, more specifically mono-oleoyl-phosphatidylethanolamine ("MOPE").